Carthamin yellow-loaded glycyrrhetinic acid liposomes alleviate interstitial fibrosis in diabetic nephropathy

To investigate the therapeutic efficacy of Carthamin yellow (CY)-loaded glycyrrhetinic acid (GA) liposomes in treating diabetic nephropathy (DN), particularly in alleviating renal interstitial fibrosis and improving kidney function. CY-loaded GA liposomes were prepared and characterized for structural stability and controlled release. DN rat models were treated with CY-loaded GA liposomes, and kidney pathology, function, collagen deposition, and TGF-β1 expression were evaluated. The effects of CY-loaded GA liposomes were compared to Vitamin E and CY alone. In vitro experiments with TGF-β1-stimulated human renal interstitial fibroblasts (hRIFs) examined the effects of CY-loaded GA liposomes on cell proliferation and the expression of fibrotic markers. Mechanistic studies assessed the role of the TGFBR1/Smad2/Smad3 pathway using TGFBR1 overexpression experiments. The CY-loaded GA liposomes exhibited a stable structure and controlled release profile. In DN rats, treatment with CY-loaded GA liposomes significantly alleviated kidney damage, improved kidney function, reduced collagen deposition and fibrosis, and downregulated TGF-β1 expression, showing superior effects compared to Vitamin E or CY alone. In TGF-β1-stimulated hRIFs, CY-loaded GA liposomes effectively suppressed cell proliferation and reduced the expression of Cyclin D1, PCNA, fibronectin, and collagen I. The inhibitory effects were stronger than CY alone and were mediated by the inactivation of the TGFBR1/Smad2/Smad3 pathway, as confirmed by TGFBR1 overexpression studies. CY-loaded GA liposomes demonstrated significant therapeutic efficacy in alleviating renal interstitial fibrosis in DN by targeting the TGFBR1/Smad2/Smad3 pathway. This novel drug delivery system provides a promising approach for the treatment of DN.

为探究载甘草次酸（glycyrrhetinic acid, GA）的红花黄色素（Carthamin yellow, CY）脂质体治疗糖尿病肾病（diabetic nephropathy, DN）的疗效，尤其是其缓解肾间质纤维化、改善肾功能的作用。本研究制备了载GA的CY脂质体，并对其结构稳定性与控释性能进行表征。构建DN大鼠模型并予以载GA的CY脂质体干预，随后评估肾脏病理状态、肾功能、胶原沉积情况及转化生长因子-β1（TGF-β1）的表达水平，并将其疗效与维生素E及单用CY进行对比。通过转化生长因子-β1刺激的人类肾间质成纤维细胞（human renal interstitial fibroblasts, hRIFs）体外模型，考察载GA的CY脂质体对细胞增殖及纤维化标志物表达的影响。借助转化生长因子β受体1（TGFBR1）过表达实验，解析TGFBR1/Smad2/Smad3通路在其中的介导作用。实验结果表明，载GA的CY脂质体结构稳定且具备可控释药特性。在DN大鼠模型中，该脂质体干预可显著减轻肾脏损伤、改善肾功能，减少胶原沉积与纤维化程度，并下调TGF-β1的表达，其疗效优于维生素E或单用CY。在TGF-β1刺激的hRIFs中，载GA的CY脂质体可有效抑制细胞增殖，降低细胞周期蛋白D1（Cyclin D1）、增殖细胞核抗原（PCNA）、纤连蛋白及I型胶原的表达水平，其抑制效果优于单用CY；且该作用通过抑制TGFBR1/Smad2/Smad3通路介导，这一点经TGFBR1过表达实验得到验证。载GA的CY脂质体可通过靶向TGFBR1/Smad2/Smad3通路，显著缓解DN中的肾间质纤维化，展现出良好的治疗潜力。本研究开发的新型药物递送系统为糖尿病肾病的临床治疗提供了极具前景的新思路。